Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394924
Title: Enhancement of intestinal absorption of peptides
Author: Wheeler, Sarah
ISNI:       0000 0001 2446 6575
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1998
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Abstract:
1. Peptide hormones, once available only through extraction from animal tissue, are now increasingly manufactured synthetically. However, the route of administration is usually by injection due to the low oral bioavailability of the hormones, as a consequence of proteolytic degradation in the small intestine, poor penetration of the intestinal mucosa, and clearance from the portal vein by the hepatocytes of the liver. 2. Since bile acids are efficiently absorbed by an active carrier system in the ileum, the present study investigated the degree to which transport of ileally-administered tetragastrin, a peptide composed of four amino acid residues, could be enhanced by coupling with cholic acid. Conjugation with cholic acid was at the position where - glycine and taurine attach naturally in the formation of conjugated bile salts. 3. In the fasted anaesthetised rat, gastric acid secretion was measured at 15 min intervals as a bioassay for the levels of tetragastrin in the blood stream. In all experiments, intravenous administration of tetragastrin or the tetragastrin-cholic acid conjugate (G-CA) was adopted as the first and final procedure, in order to demonstrate the continued viability of the animal preparation. 4. Intravenously administered tetragastrin (minimum effective dose, most commonly 15mug kg-1) as a first procedure was shown to evoke a mean peak increase in gastric acid levels of 0.50 +/- 0.06mumol 15min-1. Over a period of one hour following injection, a mean cumulative increase in gastric acid output of 1.07 +/- 0.39mumol hr-1 was demonstrated (n=31). G-CA (15ng kg-1) also demonstrated biological activity when administered intravenously: a mean peak increase in gastric acid levels of 0.50 +/- 0.18mumol 15min-1, and a mean cumulative increase of 0.91 +/- 0.47mumol hr-1 were obtained (n=32). In both cases, a broadly comparable increase in gastric acid secretion was also obtained in response to a second intravenous injection, indicating that the animal preparation was neither fatigued, nor that earlier procedures had resulted in potentiation of the response. 5. Intra-intestinal administration of tetragastrin (2500ng kg-1) was shown not to produce a measurable increase in gastric acid levels. By contrast, the present study demonstrated unequivocally that infusion of G-CA (600mug kg-1) into the ileum resulted in the stimulation of increased levels of gastric HCl secretion (means of small samples were weighted to give a true mean increase of 1.84 +/- 1.22mumol 180min-1). 6. Simultaneous infusion of tetragastrin and glycocholic acid (in a ratio of 3:2, total dose of 600mug kg-1) into the ileum did not elicit any measurable increases in gastric acid secretion, despite the solution being biologically active, as confirmed by a measurable increase in gastric acid secretion following intravenous injection (1.09 +/- 0.58mumol hr-1, P=0.033; n=5). 7. Surprisingly, instillation of tetragastrin (2500mug kg-1) into the ileum did evoke a significantly marked increase in gastric acid secretion (3.05 +/- 1.89mumol 180min-1, P=0.006; n=7), though only when tetragastrin was preceded by ileally-administered G-CA (600ng kg-1). This indicated that a possible lasting permeability change in the ileal mucosa was caused by ileal G-CA, thus permitting the permeation of the intestinal wall by tetragastrin. Nevertheless, the results of light microscopic analysis revealed little evidence of a pathological alteration to the intestinal mucosa. 8. The transmucosal movement of G-CA appeared to be specific to the ileum, as there was no evidence of transport across the jejunal mucosa following intraluminal instillation of G-CA (600mug kg-1). Subsequent administration of G-CA (600mug kg-1) in the ileum of the same rat produced a significant increase in gastric acid secretion. 9. The results of the present study are indicative of utilisation of the bile salt active transporter by G-CA. This is very encouraging in terms of a successful approach to address the facilitation of permeation of otherwise poorly absorbed oligopeptides across the intestinal mucosa and into the systemic circulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.394924  DOI: Not available
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